tbuckley/cabot-search huggingface dataset:
A functional immuno-oncology (IO) assay to assess patient response to immunotherapeutics in metastatic disease.
Authors: Shiaowen David Hsu, Joshua Hammer, Lihua Wang, Shaun Steele, Gabrielle Rupprecht, Zhaohui Wang, Steven Metzger
Journal: Journal of Clinical Oncology (2023)

e14592 Background: Immuno-Oncology (IO) therapy such as anti-PD1 and anti-CTLA4 blockade has rapidly become the standard of care in melanoma, lung, and other solid tumors. However, current biomarkers such as PDL1 expression (TPS/CPS) do not accurately predict which patients will respond to anti-PD1 therapy. There is an unmet clinical need to develop better assays to predict which cancer patients will derive benefit from anti-PD1 and anti-CTLA4 therapy. Our recently developed MicroOrganoSpheres (MOSTM) technology partitions patient tumor samples into many tiny droplets containing the patient's native tumor microenvironment, including immune cells. The patients’ MOS can then be divided across multiple test conditions, enabling the development of a functional IO assay to predict response to IO therapy. Methods: Patient tumor samples from lung, melanoma, hepatocellular carcinoma (HCC), and colorectal cancer (CRC) containing resident immune cells were partitioned into individual immunologically active MOS. Tissue digest and culture conditions were optimized to maintain native immune cell viability and functionality for 8 days, enabling immune-mediated response to immune checkpoint inhibitors to be assessed using a variety of bioanalytic methods. MOS were dosed with nivolumab/panitumumab (anti-PD1 inhibitor), atezolizumab (anti-PDL1 inhibitor), ipilimumab (anti CLTA-4 inhibitor) or an isotype control antibody (IgG). Biological response was assessed using a combination of flow cytometry, imaging, and ELISA based high-sensitivity interferon gamma (IFNy) secretion quantification. Results: Using 35 cancer specimens including lung, melanoma, ovarian and renal cell carcinoma (RCC), a functional IO assay was developed to assess cell populations within patient-derived MOS, including relevant T cell populations, and characterize IFNy secretion after exposure to immunotherapy. The assay was then validated on three patient samples with metastatic HCC, melanoma, and MSI CRC. The samples were first interrogated using the optimized immunotherapeutic assay to determine cell populations within MOS by flow cytometry, imaging including immunofluorescence labeling of cell populations, and functionality by IFNy secretion quantification, to generate aMOS IO Index (MII) with MII &lt; 1 representing no response to therapy and MII &gt; 1 representing response to therapy. Of the three samples, the HCC had a MII &lt; 1 while the melanoma and CRCr had MII &gt; 1. Each patient subsequently received either anti-PD1/PDL1 and/or anti-CTLA therapy and their response to therapy was predicted by their MII. Conclusions: These preliminary data suggest our immunotherapeutic assay represents a first-of-its-kind functional assessment that can potentially predict patient response to immune checkpoint inhibitors. Further validations of our assay are now underway in our functional precision oncology MOS IO trial.
Hints for reclassification of meningiomas based on the fifth edition of WHO CNS.
Authors: Chuandong Cheng, Tiantian Han, Didi Guo, Rongrong Kong, Siqi Chen, Yuwei Dong, Mengjuan Wang, Ran Ding, Wanglong Deng, Fanfeng Bu, Yuan Wang
Journal: Journal of Clinical Oncology (2023)

e14059 Background: Meningioma is the most common primary neoplasm of the central nervous system (CNS) in adults. Genetic variants ( NF2, AKT1, TRAF7 etc.) are strongly related to the subtypes of meningioma. TERT promoter mutation or homozygous CDKN2A and/or CDKN2B deletion are independent evidence for diagnosing WHO grade 3 meningioma according to 5 th CNS WHO. Our study reclassifies meningiomas using a clinical and molecular real-world dataset. Methods: This study retrospectively analyzed the genomic alteration of 347 Chinese meningioma patients during 2019-2022. Next-generation sequencing (NGS) was performed to detect gene mutations in tumor samples. Results: TERT promoter mutation or CDKN2A/B deletion were identified in 11% (n = 39) of patients ( TERT 5.2%, CDKN2A 8.1%, CDKN2B 8.6%). Of these cases, histologic grade information was available for 26 patients, 14(53.8%) of whom were reclassified as WHO grade 3 meningiomas, including four histologic grade 1 and ten histologic grade 2. There is a male preponderance in reclassified patients (56.4% vs. 40.0%, p &lt; 0.05), meanwhile the age showed no significant difference between them (average age: 54 vs 50, p = 0.11). The most frequently co-mutated gene was NF2. The proportion of TERT promoter mutation or CDKN2A/B deletion in NF2-mutant tumors was similar to NF2-wildtype tumors (10% vs. 11%, p &gt; 0.05). Conclusions: In our study, 11% of Chinese adult meningioma patients found TERT promoter mutation or CDKN2A/B deletion and showed a male preponderance, among 53.8% of whom were reclassified as meningiomas WHO grade 3. Overall, these data advance the understanding of the significance of molecular profiling in the classification of meningioma patients according to the 5 th WHO CNS.
Low-intensity focused ultrasound with systemic microbubble oscillators for blood-brain barrier disruption for liquid biopsy in glioblastoma (LIBERATE).
Authors: Manmeet Singh Ahluwalia, Michael W McDermott, Terry C Burns, John Frederick de Groot, John Y.K. Lee, Alon Mogilner, Theodore Schwartz, Bhavya Shah, Chetan Bettegowda, Ahmad Ozair, Atulya Aman Khosla, Arjun Sahgal, Mark V. Mishra, Achal Achrol, Nir Lipsman, Graeme Woodworth
Journal: Journal of Clinical Oncology (2023)

TPS2084 Background: Liquid biopsy in glioblastoma (GBM) is hindered by a lack of requisite circulating-free DNA (cfDNA) levels in blood due to the blood-brain barrier (BBB). This results in challenges to the identification of blood-based biomarkers and the development of novel biomarker-driven systemic therapies. Real-time image-guided low intensity focused ultrasound (LIFU) combined with IV microbubble oscillators (DEFINITY), non-invasively causes BBB disruption (BBBD). This clinical trial aims to evaluate the utility of LIFU for increasing cfDNA in blood for liquid biopsy in GBM. Methods: LIBERATE is a prospective, multi-center, self-controlled, ongoing, pivotal trial evaluating safety and technical efficacy of LIFU for BBBD to increase cfDNA in blood for GBM. Patients aged &gt;18-80 years with suspected GBM planned for tumor biopsy or resection at eleven centers in North America are being included. Patients with multifocal tumors or tumors arising from deep midline, thalamus, cerebellum, or brainstem are excluded. Patients are administered IV oscillating microbubbles for enhancing sonication, after which MR-guided BBBD using a 220 kHz LIFU device is performed with real-time acoustic feedback for effective cavitation. Before and after procedure, phlebotomies and MRI brain are performed to evaluate outcomes. The primary study endpoint is defined, per subject, as the ratio between their cfDNA level in blood 1-hour post-LIFU compared to cfDNA level in blood pre-procedure. The primary study hypothesis is that BBBD with LIFU leads to ≥2-fold increase in cfDNA in blood. The secondary hypothesis is that there exists ≥75% agreement between biomarker pattern in cfDNA sample from 1-hour post-LIFU sample and biomarker pattern in tumor tissue obtained later. The trial has been powered to evaluate both primary and secondary hypotheses. Based on an assumed true agreement rate of 91% and a one-sided alpha of 0.025, an exact test for binomial proportions provides a sample of N=50 with 84% power for the secondary hypothesis. Exploratory endpoints include (1) sensitivity of detection of known somatic mutations in cfDNA from blood samples collected before and after LIFU, (2) estimation of cfDNA levels post-LIFU in samples collected at 30 minutes, 1 hour, 2 hour, and 3 hour to determine time of greatest yield, (3) correlation of MRI parameters related to grading of BBBD and biomarkers positive in cfDNA from post-LIFU blood samples. Patient enrollment commenced in 2022 and 7 patients have been recruited by 02/13/2023. Clinical trial information: NCT05383872 .
TIGIT transcriptomic expression and high levels of multiple checkpoints across diverse cancers.
Authors: Jacob J. Adashek, Shumei Kato, Sarabjot Pabla, Mary K Nesline, Jeffrey M. Conroy, Paul DePietro, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2023)

e14637 Background: The T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is an immune inhibitory receptor present on some T- and natural killer (NK) cells. It plays an important role in restricting innate and adaptive immunity. Given this, studies to combine other checkpoint inhibitors with anti-TIGIT therapies are currently in development. Methods: The RNA expression levels of 397 genes in various types of solid tumors from 514 patients seen at the UCSD Moores Cancer Center were analyzed at a CLIA-licensed laboratory, (OmniSeq (https://www.omniseq.com/)). Transcript abundance was normalized to internal housekeeping gene profiles and ranked (0-100 percentile) in a standardized manner to a reference population of 735 tumors spanning 35 histologies. Odds ratio for high TIGIT expression (≥75 percentile rank) was calculated and Bonferroni corrected for multiple genes and cancer histologies with &gt; 10 samples. Results: Of 514 tumors, 99 (19%) tumors had high TIGIT expression (32 different histologies). Cancers with the greatest proportion of high TIGIT expression were small intestine (33%; 4/12) pancreatic (31%; 17/55), lung (25%; 5/20), stomach (20%; 5/25), breast (20%; 10/49), colorectal (18%; 25/140), head and neck (17%; 2/12), sarcoma (13%; 3/24), and uterine (13%; 3/23), though there were no statistically significant associations between these histologies and high TIGIT. There were significant associations between high TIGIT and high PD-L1 (P &lt; 0.0021), PD-1 (P &lt; 0.0021), PD-L2 (P &lt; 0.0021), CTLA-4 (P &lt; 0.0021), OX40 (P &lt; 0.0021), LAG3 (P &lt; 0.0021), FOXP3 (P &lt; 0.0021) expressions (p values Bonferroni adjusted for multiple comparisons). However, there was no significant association between tumor mutation burden ≥10 mutations/mb and high TIGIT. Conclusions: High TIGIT expression was found in 19% of 514 tumors (pan-cancer) and significantly associated with high RNA expression of other immune checkpoints (PD-L1, PD-1, PD-L2, CTLA-4, OX40, LAG3, FOXP3), many of which can be targeted by FDA-approved drugs or drugs in clinical trials. Ongoing studies combining TIGIT inhibitors and specific immune checkpoint inhibitors may yield more clinical benefit after personalized tumor immune profiling.
Doxorubicin to enhance the abscopal effect depending on tumor cell mitochondrial DNA and cGAS/STING.
Authors: Liqun Wang, Ren Luo, Kateryna Onyshchenko, No Firstname Gabriele.Niedermann@Uniklinik-
Journal: Journal of Clinical Oncology (2023)

e14616 Background: Localized radiotherapy (RT) can cause a T cell-mediated abscopal effect on non-irradiated tumor lesions, especially in combination with immune checkpoint blockade (ICB). However, this effect is still clinically rare and improvements are highly desirable. We investigated whether triple combination with a low dose of clinically approved liposomal doxorubicin (Doxil) could augment abscopal responses compared with RT+ICB, Doxil+ICB, or RT+Doxil. Methods: We used Doxil in combination with RT and αPD1 in two tumor models (B16-CD133 melanoma and MC38 colon carcinoma) with mice bearing two tumors, only one of which was irradiated. Results: Triple therapy with RT, αPD1, and single low-dose Doxil strongly enhanced the RT-induced abscopal effect compared to all double and single treatments in both tumor models ( p &lt; 0.05, n = 5-10 mice/group). Complete cures of non-irradiated tumors were mainly observed in triple-treated mice. Triple therapy induced more cross-presenting dendritic cells (DCs) and tumor-specific CD8 T cells than RT/αPD1 and Doxil/αPD1 ( p &lt; 0.05, n = 5 mice/group), particularly in non-irradiated tumors. CD8 T cell depletion or implanting STING-deficient tumor cells abolished the abscopal effect. By using inhibitors and knockout cells, we show that doxorubicin/Doxil-induced IFNβ1 markedly depended on the cGAS/STING pathway ( p &lt; 0.05) which drives antitumor CD8 T cell responses through cross-presenting DCs. In mitochondrial DNA (mtDNA)-depleted tumor cells, doxorubicin/Doxil induced less IFNβ1 ( p &lt; 0.05), the related T cell-recruiting chemokine CXCL10 ( p &lt; 0.0001), and ATP ( p &lt; 0.0001); coincubation with mtDNA-depleted tumor cells strongly reduced IFNβ1 ( p &lt; 0.01) secretion by DCs. Implantation of mtDNA-depleted tumor cells, particularly at the non-irradiated site, substantially diminished the Doxil-enhanced abscopal effect and tumor infiltration by tumor-specific CD8 T cells ( p &lt; 0.05). Conclusions: Single low-dose Doxil can substantially enhance the RT-induced abscopal effect, with a strong increase in cross-presenting DCs and CD8 tumor-specific T cells particularly in abscopal tumors compared with RT/αPD1 and Doxil/αPD1. The mtDNA/cGAS/STING/IFN-I axis is important for the immunogenic doxorubicin effects. Our ﬁndings may be helpful for the planning of clinical radiochemoimmunotherapy trials in (oligo)metastatic patients.
Adrenal insufficiency in patients on immune checkpoint inhibitors: An All of Us Data study.
Authors: Rahman Adesoji Olusoji, Yong Eun, Rajaa Mohamed Salih, Noah Osei, Meena Ahluwalia
Journal: Journal of Clinical Oncology (2023)

e14675 Background: Immune Checkpoint Inhibitors have revolutionized the management of cancers. Several cases are reported about their adverse effects, which include adrenal insufficiency, a life-threatening irreversible sequela in some patients. Little has been done to evaluate the burden of this adverse effect on cancer patients. This study aimed to measure the incidence rate of adrenal insufficiency in patients on immune checkpoint inhibitors in the United States using the All Of Us database. Methods: In this cross-sectional study, we included participants from the All of Us dataset version 6, which includes data collected between May 6, 2018, and January 1, 2022, who had available Electronic Health Records data (N = 258,188). We defined the cancer cohort as having at least one ICD-9/ICD-10 diagnostic code for cancer. We identified participants in the cancer cohort without or with at least one exposure to immune checkpoint inhibitors nivolumab, pembrolizumab, cemiplimab, ipilimumab, atezolizumab, avelumab, durvalumab, tremelimumab, relatlimab, tremelimumab, pidilizumab. Adrenal insufficiency was defined as having one or more ICD-9/ICD-10 codes for any adrenal insufficiency after treatment with immune checkpoint inhibitors. The calculation for the Relative Risk(RR) was with unconditional maximum likelihood estimation. Results: Among 36,377 individuals diagnosed with cancer, 418 patients had exposure to immune checkpoint inhibitors. 44(10.5%) of the 418 were diagnosed with adrenal insufficiency after exposure to immune checkpoint inhibitors. The relative risk of adrenal insufficiency after the commencement of an immune checkpoint inhibitor is five times that of patients not on immune checkpoint inhibitors. (RR 5.43, 95% CI 4.07-7.25, P &lt; 0.05). Conclusions: Our result suggests a higher incidence of adrenal insufficiency in cancer patients on immune checkpoint inhibitors compared to cancer patients, not on immune checkpoint inhibitors. Future prospective studies will be needed to confirm this finding. Physicians, particularly oncologists and endocrinologists, should have a high index of suspicion for adrenal insufficiency in patients on immune checkpoint inhibitors.
The ketogenic diet plus standard of care for adults with recently diagnosed glioblastoma: Results from a phase 1 trial.
Authors: Lj Amaral, Gillian Gresham, Sungjin Kim, Mourad Tighiouart, Thomas Nelson, Amelia Welborn, Laura Lockshon, Brandon Noorvash, Jeremy David Rudnick, Scott A Irwin, Stephen J. Freedland, Jethro Lisien Hu
Journal: Journal of Clinical Oncology (2023)

2076 Background: Facing limited treatment options, brain tumor patients are often highly motivated to use complementary therapies, including diet, to help themselves. There is now an abundance of preclinical evidence suggesting possible benefit with a ketogenic diet (KD) for brain tumor patients, but clinical evidence is still limited. Thus, we conducted a single-arm, phase 1 safety and feasibility trial of a KD among patients with recently diagnosed glioblastoma (GBM) during standard- of-care (SOC) treatment. Methods: Adults with GBM within 3 months of diagnosis followed a supervised 16-week diet intervention of a standard 3:1 KD (Fat(g):Carbohydrate+Protein(g)) plus SOC chemoradiation. Primary outcome was safety, evaluated by weekly assessments of weight and body mass index (BMI). Secondary outcomes included feasibility (pre-specified as &gt; 50% of patients maintaining blood ketone levels &gt; 0.3 mM over 50% of study days), progression-free survival (PFS), overall survival (OS), health-related quality-of-life (QOL), and cognitive function. Twice daily blood glucose and ketone levels, weight/BMI, physical activity, and sleep were assessed by remote monitoring. Results: Seventeen patients were evaluable: 53% women, median age 55, median Karnofsky Performance Status 85. All participants met the primary safety objective with no instances of excessive weight loss or related serious adverse events. Adherence to KD was high: all 17 patients maintained nutritional ketosis (≥0.3 mM/dL) &gt;50% of study days, where 14 patients maintained nutritional ketosis &gt;85% of study days. Median time to ketosis from diet initiation was 3 days. Diet-related AEs were mild and manageable; no patients came off study due to inability to tolerate KD. Median progression-free survival (PFS) and overall survival (OS) were 12.5 months and 28.6 months from KD initiation respectively. QOL, symptom control, and cognitive function remained stable or improved, although these did not reach statistical significance. Conclusions: This phase 1 trial demonstrates that KD is safe and feasible for GBM patients receiving SOC, may improve outcomes, and provides a foundation for future randomized trials to assess efficacy. Clinical trial information: NCT03451799 .
Adverse events (AEs) of immune checkpoint therapy (ICT) combined with vascular endothelial growth factor inhibitors (VEGFi) vs. ICT alone: A pooled meta-analysis of 1735 patients.
Authors: Iuliia Kovalenko, Wern Lynn Ng, Yimin Geng, Raed Benkhadra, Pavlos Msaouel, Omar Alhalabi
Journal: Journal of Clinical Oncology (2023)

e14667 Background: ICT combined with VEGFi are established as approved therapies for multiple malignancies. However, added toxicities remain unclear. We hypothesized that the combination of ICT + VEGFi has higher treatment-related AEs (TRAEs) and immune-related AEs (irAEs) compared with ICT alone. Methods: We performed a meta‐analysis to identify studies evaluating toxicity profile of ICT + VEGFi as compared to ICT. Systemic search was performed across all cancer types and major databases until August 10, 2022. Search structures, subject headings, and keywords were tailored to databases by medical research librarian. Screening of studies was done by two investigators. Inclusion criteria consisted of prospective phase II or III clinical studies which included at least one arm of patients treated with ICT + VEGFi and one arm treated with ICT alone. Restricted maximum likelihood fixed effects model was used to pool AEs data; I2 was used for heterogeneity. Results: From a total of 9366 studies found, seven met inclusion criteria. A total of 808 patients were treated with ICT while 927 were treated with ICT + VEGFi. Only one study reported irAEs. Therefore, we restricted our analysis to TRAEs. The total number of TRAEs (including grade 5) was significantly higher in ICT + VEGFi group with more frequent treatment withdrawals attributed to TRAEs. The list of TRAEs and specific effect sizes are summarized. The highest TRAE effect size increases with ICT + VEGFi were noted for rash (RR 6.50), hypertension (RR 6.07), hypothyroidism (RR 5.02), and diarrhea (RR 4.94). Conclusions: Combination therapy with ICT + VEGFi confers increased risk of specific TRAEs in comparison to ICT. Clinicians should be particularly mindful of the increased risk for rash, hypertension, hypothyroidism, diarrhea, nausea, anorexia, and proteinuria with ICT + VEGFi therapies. There are insufficient data on irAEs and future trials should provide more granular details on the AE cause. [Table: see text]
Replacement of anti-PD-1 drugs with prolgolimab during treatment, safety and efficacy.
Authors: Timur Andabekov, Elena Napolskaia, Maria Rodina, Alina Khlobystina, Elizaveta Gulo
Journal: Journal of Clinical Oncology (2023)

e14701 Background: The anti-PD-1 treatment has been shown good response in patients with cancer. There is little information in open sources on the possibility of changing anti-PD-1 drugs during treatment for non-medical indications. Prolgolimab (formerly BCD-100) is an IgG1 anti–PD-1 mAb that contains the Fc-silencing mutation LALA, which provides an immunopotential advantage by eliminating the interaction between the Fc region of the antibody and FcyR expressed on various immune cells, thus blocking possible effector functions of the antibody. We report the replacement of anti-PD-1 drugs during treatment on safety and anti-PD-1 response in patients with melanoma and lung cancer. Methods: 5 patients with advanced melanoma and 2 non small cell lung cancer (NSCLC) with RECIST-evaluable disease, with prior anti-PD-1 treatment by nivolumab and pembrolizumab. 5 Patients were with prior anti-PD-1 treatment by nivolumab (median duration of treatment was 4 months) and 2 patients pembrolizumab (median duration of treatment was 7 months). Patients were treated (replaced) with prolgolimab (anti-PD-1) 1 mg/kg every 2 week. The primary objective was safety of replacement anti-PD-1 therapy and objective response rate (ORR) by RECIST 1.1. Replacement of anti-PD-1 drugs during treatment were associated for non-medical indications. Patients were with ECOG 0-1. Results: Median age was 57 years, 5 were male, 1 patients with NSCLC had a KRAS mutation and patients with melanoma had a BRAF mutation. Median follow-up was 10 months. Adverse events continued after prescription of prolgolimab. New adverse events have not experienced. Anti-PD-1 therapy was not discontinued. ORR was 85%, of which 3 were CR. Median PFS was not reached. 1 patient with NSCLC prior anti-PD-1 treatment by nivolumab (2 cycles 480 mg) had PD, but PR was prolgolimab. Conclusions: Anti-PD-1 treatment followed by prolgolimab (anti-PD-1) in our patients undergoing therapy is safe and does not worsen anti-tumor responses. We assume that in certain situations it is possible to make (for example, individual intolerance) substitutions of drugs in the same group anti-PD-1 Replacement anti-PD-1 may reduce financial toxicity.